Shistosomiasis continues to be a major helminthic disease suffered by millions of people throughout the world. Morbidity and mortality are largely due to the consequences of a host CD4 T cell-mediated immune response against parasite egg antigens, yet the magnitude of the resulting granulomatous and fibrosing inflammation varies greatly from individual to individual, and also among inbred mouse strains in an experimental model of the disease. In the majority of individuals, in whom the egg antigen-specific CD4 T cell response readily attains effective Th2 polarization, there is relatively limited immunopathology with improved survival; conversely, an unrelenting pro-inflammatory Th1 milieu is conducive to severe disease and death. To date, the failure of some to turn off the life-threatening Th1 response is still not clear. The studies proposed in this application will examine two plausible mechanisms that drive Th1 responses with the hypothesis that both contribute to the development of the pronounced immunopathology typically seen in the C3H and CBA mouse strains. The first is the production of IL-12 by dendritic cells derived from normal (CBA) mice and the second is an oligoclonal expansion of a CD4 T cell population reacting against the immunodominant epitope 234-246 (Sm-p40234-246) of the major Sm-p40 schistosome egg antigen with a Th1-biased response. Aim 1 of this proposal examines the pathogenicity of IL-12 and related cytokines; Aim 2 examines the pathogenic role of CD4 T cells that recognize Sm-p40234-246 with focus on a transgenic mouse expressing a T cell receptor specific for this epitope, and Aim 3 assesses the relative contribution of these two mechanisms with the use of MHC congenic mice. These studies will provide a better understanding of the major pathways leading to severe immunopathology in murine schistosomiasis. They should lead to the design of highly focused, realistic and practical strategies for amelioration of disease, which could be amenable for consideration and possible implementation in the human patient population.